Cyclosporine-A is a new drug used primarily in patients who undergo organ transplant, but also in the treatment of rheumatoid arthritis, psoriasis, type I diabetes mellitus, systemic lupus erythematosis and multiple sclerosis. It is estimated that one billion persons worldwide will be treated with cyclosporine-A (CS-A) within the next decade. A side effect of CS-A is enlargement and overgrowth of the gingivae; related side effects include renal and cardiac interstitial fibrosis. Virtually nothing is known about the epidemiology, treatment or prevention of CS-A induced gingival overgrowth, nor about the pathogenesis of the lesion at cellular and molecular levels. In a multinational human clinical study involving over 400 volunteers, the incidence and prevalence of CS-A induced gingival overgrowth will be determined. The possibility that lesion severity is correlated with patient age, sex or race, or with saliva and blood drug levels, or with degree of gingival inflammation or T-lymphocyte response will be ascertained. Professional and personal oral hygiene as therapy for CS-A induced gingival overgrowth will be evaluated quantitatively in the longitudinal study. In a series of in vitro studies of human gingival and renal fibroblasts, the effects of CS-A on protein and collagen production, glycosaminoglycan accumulation, collagen types synthesized, cell proliferation, viability, chemotaxis and attachment will be evaluated. Effect on CS-A on DNA synthesis by gingival and renal fibroblasts will also be determined. Fibroblast replicative lifespan in the presence of CS-A will be measured. The qualitative and quantitative composition of CS-A enlarged human gingival tissue will be ascertained by means of histomorphometric (stereologic) analysis. Successful completion of the proposed research will provide physicians and dentists with new knowledge that will be of immediate and long-term public health benefit. In addition, the information gleaned concerning the cellular and molecular nature of the fibrotic gingival side effect of CS-A, and its biochemical and structural relation to the kidney lesions also elicited by the drug, is likely to shed direct new light on life-threatening exigencies in man; thus, the results of the proposed oral health research may have additional significant public health benefit beyond the oral cavity.